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Why Oxford’s Positive COVID Vaccine Results Are Puzzling Scientists

Preliminary data suggest that the immunization was more effective in trial participants who received a lower dose.

A highly anticipated COVID-19 vaccine has delivered some encouraging — but head-scratching — results. The vaccine developed by the University of Oxford, UK, and pharmaceutical giant AstraZeneca was found to be, on average, 70% effective in a preliminary analysis of phase III trial data, the developers announced in a press release on 23 November.

But the analysis found a striking difference in efficacy depending on the amount of vaccine delivered to a participant. A regimen consisting of 2 full doses given a month apart seemed to be just 62% effective. But, surprisingly, participants who received a lower amount of the vaccine in the first dose and then the full amount in the second dose were 90% less likely to develop COVID-19 than were participants in the placebo arm.

Earlier this month, drug companies Pfizer and BioNTech reported that their RNA-based vaccine was around 90% effective after the trial reached its primary endpoint, and an interim analysis of an RNA vaccine by biotechnology firm Moderna showed it worked roughly as well.

Researchers caution against making head-to-head comparisons of vaccines on the basis of incomplete data. The disparity in the latest results means there will be considerable uncertainty over precisely how well the Oxford vaccine protects against COVID-19 until ongoing efficacy trials report more data, say scientists. “We’re slightly in danger of rushing to compare apples and oranges,” says Daniel Altmann, an immunologist at Imperial College London. “There’s a long, long way to go before these data settle down and get reported and published in full.”

Viral vector

The Oxford–AstraZeneca vaccine is made from a cold-causing adenovirus that was isolated from the stool of chimpanzees and modified so that it no longer replicates in cells. When injected, the vaccine instructs human cells to produce the SARS-CoV-2 spike protein — the immune system’s main target in coronaviruses. The vaccine entered phase III efficacy trials before other front runners, including Pfizer and Moderna, and trials are continuing in countries including the United States, South Africa, Japan and Russia. The 23 November analysis is based on 131 COVID-19 cases among more than 11,000 trial participants in the United Kingdom and Brazil, up to 4 November.

Overall, the developers found that the 2-dose vaccine had an efficacy of 70%, when measured 2 weeks after participants received their second dose. But that figure is an average of the 62% and 90% efficacy from the two dosing regimens. “90% is pretty good, but the 62% for the second tested regimen are not that impressive,” said Florian Krammer, a virologist at Icahn School of Medicine at Mount Sinai in New York City, on Twitter.

A top priority for researchers is understanding why the vaccine seems to have performed so much better with a lower first dose. One explanation could lie in the data: the trial might not have been big enough to gauge the differences between the two regimens, in which case the differences might vanish once more cases of COVID-19 are detected, says Luk Vandenberghe, a virologist at the Massachusetts Eye and Ear institute and Harvard Medical School in Boston. The more effective ‘half-dose, full dose’ results were based on 2,741 trial participants, whereas the less efficacious arm included 8,895 volunteers. The press release did not specify in which group cases occurred.

On the basis of the data, Stephen Evans, a statistical epidemiologist at the London School of Hygiene & Tropical Medicine, estimates that the ‘half-dose, full dose’ regimen could have an efficacy as low as 66%.

Dosing theories

But, if the differences are real, researchers are eager to understand why. “I don’t think it’s an anomaly,” says Katie Ewer, an immunologist at Oxford’s Jenner Institute who is working on the vaccine. “I’m keen to get into the lab and start thinking about how we address that question.” She has two leading theories for why a lower first dose might have led to better protection against COVID-19. It’s possible that lower doses of vaccine do a better job at stimulating the subset of immune cells called T cells that support the production of antibodies, she says.

Another potential explanation is the immune system’s response to the chimpanzee virus. The vaccine triggers a reaction not only to the SARS-CoV-2 spike protein, but also to components of the viral vector. It’s possible that the full first dose blunted this reaction, says Ewer. She plans to look at antibody responses to the chimpanzee virus to help address this question.

“This is a plausible explanation,” says James Wilson, a virologist at the University of Pennsylvania in Philadelphia who pioneered the use of adenoviruses for vaccines in the 1990s. By giving a half-dose first, “it is possible that AstraZeneca threaded the needle with their dosing”, he adds.

Hildegund Ertl, a viral immunologist at the Wistar Institute in Philadelphia, says the results make sense in the light of some of her work on adenovirus vaccines in mice. She, too, has found that for a two-dose vaccine, a low first dose can lead to better protection than a high first dose. She thinks this is because a lower first dose leads more quickly to the establishment of ‘memory’ immune cells that are triggered by a second-dose boost. Waiting longer between the two doses could achieve the same effect.

AstraZeneca hopes to gather more data on the dosing regimen. The company has so far given the vaccine to around 10,000 participants in a US arm of the efficacy trial, which was paused for more than a month starting in September, while researchers investigated a neurological condition in a UK trial participant.

The company plans to ask regulators whether it can modify the trial to include the more efficacious dosing regimen, said Mene Pangalos, vice-president of biopharmaceuticals research at AstraZeneca, which is based in Cambridge, UK, at a press briefing.

“It would be madness to use more vaccine than you needed to get less efficacy,” says Ewer. “I think we will see a move towards roll-out of the ‘low dose, standard dose’ regime.”

Hints of optimism

While Oxford and AstraZeneca make sense of their trial data and gather more, there is reason for optimism in other facets of the vaccine’s performance, say scientists. No participants who received the vaccine were hospitalized or developed severe COVID-19, suggesting the vaccine might do a good job at preventing severe disease.

There were also hints that the vaccine might prevent infected people from transmitting the virus, even if they aren’t showing symptoms. In the trial’s UK arm, some participants routinely swabbed themselves for SARS-CoV-2 testing, even if they weren’t showing symptoms. Differences in infection rates between people who received the placebo and those who got the Oxford vaccine suggest the vaccine blocks transmission, says Ewer. (The Pfizer and Moderna trials tested only people who showed symptoms.)

Even with a question mark hanging over its efficacy, the Oxford–AstraZeneca vaccine could see wider roll-out than some other COVID-19 immunizations. The vaccine is stable at refrigerator temperatures, in contrast to the Pfizer and BioNTech vaccine, which must be stored at −70 ºC until hours before vaccination.

And more of the vaccine could be available sooner, relative to other jabs. AstraZeneca estimates that it will have 200 million doses ready worldwide by the end of 2020, and capacity to produce 100 million to 200 million doses per month once production is ramped up, according to Pam Cheng, vice-president for operations and information technology at AstraZeneca.

“The battle really between all these vaccines is going to be really a logistical one,” says Vandenberghe. “We will be able to use every dose that becomes available.”


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